Human systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease with involvement of multiple organ systems and extremely diverse clinical manifestation. SLE appears to involve the emergence and activation of both autoreactive T cells and B cells. Our preliminary data suggest that Fas (CD95) mRNA has been modified in SLE patients. The first Fas mRNA modification (or editing) resulted in an insertion of A after nucleotide 1114 (Genbank accession number X63717) that leads to a frameshift mutation in the Fas coding region and disruption of the death domain in Fas protein. Up to 26% of edited Fas mRNA has been found in SLE patients. The second Fas mRNA editing event resulted in a T to C substitution at nucleotide position 1173 that leads to an amino acid change from isoleucine to threonine mutation within the death domain of Fas protein. The latter editing event has been detected both in SLE patients and non-SLE controls. Furthermore, we have also detected two non-synonymous polymorphisms in a group of SLE patients. The first non-synonymous polymorphism occurs at the Fas signal sequence cleavage site and the second non-synonymous polymorphism is within the Fas transmembrane domain. These Fas polymorphisms potentially will alter Fas biological functions. Accordingly, the overall goals of this project are to identify and characterize mutations resulting from Fas mRNA editing in SLE patients and from novel Fas gene polymorphisms and to determine whether these mutations and polymorphisms in Fas have an impact on the pathogenesis of SLE. These goals will be achieved through the following specific aim: 1) to confirm the existence of altered Fas mRNA editing products and their impact on Fas protein expression and on Fas functions; 2) to investigate whether the editing of Fas mRNA occurs uniquely in SLE or occurs also in other inflammatory diseases; 3) to detect and characterize Fas coding region non-synonymous polymorphisms and/or mutations in SLE population; 4) to establish the potential role of Fas mRNA editing and polymorphisms or mutations in human SLE pathogenesis. Elucidation of the biological roles of Fas editing and polymorphisms in the pathogenesis of SLE will aid the development of new therapeutic a roaches for SLE.